乳酸调控肿瘤微环境PD-1/PD-L1信号轴的研究进展

The research development of PD-1/PD-L1 signaling axis regulated by lactate in tumor microenvironment

肿瘤细胞Warburg效应消耗大量葡萄糖并产生过量乳酸。由于肿瘤特殊脉管结构,易形成局部乳酸堆积,肿瘤微环境高浓度乳酸不仅直接抑制免疫细胞功能,还可作为信号分子募集免疫抑制相关细胞,调节免疫检查点信号轴,进而促进肿瘤发展。本综述将重点关注乳酸对肿瘤细胞及肿瘤相关基质细胞PD-1/PD-L1信号轴的调控作用及机制。同时,我们也关注到乳酸产生关键酶乳酸脱氢酶(lactate dehydrogenase,LDH)在程序性死亡受体1(programmed death 1,PD-1)/程序性死亡受体-配体1(programmed cell death-ligand 1,PD-L1)免疫检查点阻断治疗中的应用,这可能使靶向LDH成为提高PD-1/PD-L1检查点阻断治疗疗效的新思路。

Tumor cells consume glucose and release excessive lactate due to the Warburg effect.Locally lactate buildup in the tumor microenvironment results from special tumor vasculature,which directly suppresses functions of immune cells.High concentrations of lactate can also act as a signaling molecular to drive tumor development through recruitment of cells that are associated with immunosuppression and regulation of immune checkpoint axis.This review will focus on regulation and mechanisms of lactate action on PD-1/PD-L1 axis of tumor and tumor-associated stromal cells.In the meantime,we realize that the application of lactate dehydrogenase,the critical lactate biosynthetic enzyme,in PD-1 and PD-L1 immune checkpoint blocking therapy,which may make targeted LDH a new strategy to improve the efficacy of PD-1/PD-L1 blockade therapy.